Human herpesvirus 8 (HHV-8) is the etiologic agent of KS, the most common cancer associated with HIV infection and AIDS. We hypothesize that T cell immunity is critical to control of HHV-8 infection and prevention of KS, and that this is linked to interactions with HHV-8 infected, professional antigen presenting cells (APC), particularly blood and tissue dendritic cells (DC) and B cells. We and others have shown that anti-HHV-8 T cell immunity is present in HIV infected and non-HIV infected persons who are seropositive for HHV-8. We have also shown that DC and B cells can be infected with HHV-8, but only activated B cells support complete virus replication, and that infection of all three cell types requires DC-SIGN. However, we know little regarding anti- HHV-8 T cell-APC interactions in controlling viral infection and disease. For the next 5 years of this grant, we propose to define several immunologic interactions of DC with anti-HHV-8 CD8 T cells. In Aim 1, we will define primary and secondary T cell responses to HHV-8 lytic and latency proteins. We will address the role of the major types of myeloid DC - monocyte-derived DC, Langerhans cells and dermal DC, and B cells - in priming nave CD8 T cells and activation of memory T cells using HHV-8 peptide libraries, whole virus and HHV-8 infected apoptotic B cells. In Aim 2, we will compare primary and secondary T cell responses in our unique cohort of HIV negative and positive persons who seroconverted to HHV-8 in the Multicenter AIDS Cohort Study (MACS). We will assess nave CD8 T cells obtained prior to seroconversion to HHV-8 with memory T cells obtained longitudinally after HHV-8 seroconversion for responses to HHV-8 peptide epitopes defined in Aim 1, including MACS participants who developed KS. In Aim 3, we will identify cytokines/chemokines induced by viral infection and determine their role in inhibiting expression of DC-SIGN and other C-type lectin receptors. We will construct HHV-8 recombinants deficient for expression of K3 and/or K5 in order to determine the effect of these proteins on expression of DC-SIGN and MHC class I, and on stimulation of anti-HHV-8 CTL. This research will provide important information for development of adequate treatment and prevention strategies for HHV-8 infection and related cancers. PUBLIC HEALTH RELEVANCE: Human herpesvirus 8 (HHV-8), or Kaposi's sarcoma (KS) associated herpesvirus, is the etiologic agent of KS, the most common cancer associated with HIV infection and AIDS. We propose to study the role of antigen presentation and T cell immunity in control of HHV-8 infection and prevention of KS. This study will provide important information on CD8 T cell immunity during HHV-8 infection for development of adequate treatment and prevention strategies for HHV-8 related cancers.